Reducing the Burden of Influenza After Solid-Organ Transplantation

Influenza Clinical Trial

— STOP-FLU  

Official title:

Reducing the Burden of Influenza After Solid-Organ Transplantation: the STOP-FLU Trial [Swiss Trial in Solid Organ Transplantation on Prevention of Influenza]

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03699839
• Other study ID #: 2017-01922
• Status: Completed
• Phase: Phase 2/Phase 3
• Start date: October 26, 2018
• Est. completion date: August 15, 2020

Study information

• Verified date: December 2020
• Source: University of Lausanne Hospitals
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Influenza is associated with significant morbidity and mortality in solid-organ transplant (SOT) recipients and it is mainly prevented by seasonal influenza vaccination. Unfortunately, the immunogenicity of standard influenza vaccine is suboptimal in this population. Vaccination with a high-dose (HD) influenza vaccine or an MF59-adjuvanted (MF59a) vaccine have significantly reduced the incidence of influenza and increased the immunogenicity of influenza vaccine in the elderly. The investigators will compare the immunogenicity and efficacy of two new vaccination strategies, consisting in vaccination with a HD influenza vaccine or an MF59a influenza vaccine, to the standard-dose non-adjuvanted vaccination (standard of care) in a population of SOT recipients.

Description:

Objectives: The primary objective of this study is to compare the immunogenicity of two novel vaccination strategies, consisting in vaccination with a HD influenza vaccine or an MF59a influenza vaccine, to the standard-dose non-adjuvanted vaccination (standard of care) in a population of SOT recipients.

The main secondary objectives are to evaluate the efficacy of the novel vaccination strategies in reducing the incidence of influenza, to correlate the humoral responses to vaccination with protection from influenza and to assess the influence of immunosuppression on influenza vaccine responses.

Safety objectives include the assessment of the reactogenicity of the different vaccines and to describe the incidence of acute rejection and the development of anti-Human Leucocyte Antigens (HLA) antibodies after vaccination.

Study design: Prospective double-blinded randomized controlled three-arm parallel group superiority multicenter trial.

Inclusion / Exclusion criteria: Study participants will be enrolled among ≥18-year old stable SOT recipients ≥3 months after transplantation, regularly followed at their respective outpatient clinic at the 7 transplant centers and scheduled to receive the annual influenza vaccine. Candidates will be excluded in case of previous severe reaction or allergy to one of the study vaccines or in case of treatment for acute rejection, among others.

Measurements and procedures: At day 0, after giving informed consent, eligible patients will be randomized in a 1:1:1 ratio into 3 arms: standard quadrivalent intramuscular vaccine (control), HD trivalent vaccine and MF59a trivalent vaccine. After vaccination participants will be followed for a period of 6 months. Safety will be assessed immediately after vaccination and 7, 28 and 180 days after vaccination, and blood sampling for immunogenicity analysis will be performed at baseline, 7, 28 and 180 days after vaccination. Additionally to evaluate the vaccine safety, anti-HLA antibodies will be measured at baseline and at days 28 and 180 after vaccination. Hemagglutinin titers will be determined by hemagglutination inhibition assay (HIA) according to standardized methods. During the influenza season, the development of influenza will be systematically assessed by polymerase chain reaction (PCR) by surveillance nasopharyngeal swab.

Study Product / Intervention: The study intervention consists in the intramuscular administration of either a HD vaccine (containing 60 µg of antigen of each of the three viral strains) [Fluzone-HD®] or a MF59a vaccine (containing 15 µg of antigen of each of the three viral strains with a MF59 adjuvant) [Fluad®].

Control Intervention: The control intervention consists in the administration of the standard quadrivalent non-adjuvanted intramuscular influenza vaccine (VaxigripTetra®), containing 15 µg of each of the four viral strains.

Number of Participants with Rationale: The investigators plan to enroll 780 patients (260 patients per study group). Sample size was calculated to find a significant difference between the three groups for the primary endpoint. The lowest seroconversion rate of 46% for standard dose, a mid seroconversion rate of 59% with MF59a vaccine, and the highest seroconversion rate of 70% with HD vaccine has been assumed. A 10% drop out rate is assumed and the number of patients has been rounded up to get balanced groups. In each group 260 patients are required which amounts to 780 patients.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 619
• Est. completion date: August 15, 2020
• Est. primary completion date: August 15, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Provision of written, informed consent

• Age =18 years

• Stable outpatients based on clinical judgement

• = 3 months after solid organ transplantation

Exclusion Criteria:

• Known hypersensitivity to any component (antigen, adjuvant, excipient or preservative) of study vaccines; the composition of the study vaccines is as follows:

• VaxigripTetra®: hemagglutinin, egg protein, formaldehyde, octylphenol ethoxylate/octoxynol 9 (Triton® X-100), neomycin

• Fluad®: hemagglutinin, neuraminidase, egg protein, squalene, polysorbate 80, sorbitan trioleate, sodium citrate, citric acid, kanamycin sulphate, neomycin sulphate, barium sulphate, formaldehyde, cetyl trimethylammonium bromide

• Fluzone-HD®: hemagglutinin, egg protein, formaldehyde, octylphenol ethoxylate/octoxynol 9 (Triton® X-100)

• Previous life-threatening reaction to influenza vaccine (i.e. Guillain Barré Syndrome)

• Ongoing therapy for rejection (including steroid pulse or prednisone > 2mg/kg/day over more than 14 days)

• Ongoing therapy with intravenous immunoglobulin (IVIG) and/or eculizumab

• Current or past (within 6 months) therapy with rituximab

• Abo incompatible transplantation

• Unable to comply with study protocol

• Pregnancy or breastfeeding

Related Conditions & MeSH terms

• Influenza
• Influenza, Human
• Organ Transplantation

Intervention

Biological:
• High-dose influenza vaccine
The experimental intervention consists in an intramuscular injection of a MF59-adjuvanted trivalent inactivated influenza vaccine containing 15 µg of antigen per strain (Fluad®) or an intramuscular injection of trivalent inactivated influenza vaccine containing 60 µg of antigen per strain (Fluzone-HD®) and will be performed at day 0.
• MF59-adjuvanted influenza vaccine
The experimental intervention consists in an intramuscular injection of a MF59-adjuvanted trivalent inactivated influenza vaccine containing 15 µg of antigen per strain (Fluad®) or an intramuscular injection of trivalent inactivated influenza vaccine containing 60 µg of antigen per strain (Fluzone-HD®) and will be performed at day 0.
• Standard intramuscular influenza vaccine
The control intervention consists in an intramuscular injection of one dose of VaxigripTetra®, the standard non-adjuvanted intramuscular influenza vaccine (as routinely done).

Locations

Country	Name	City	State
Spain	Hospitales Universitarios Virgen del Rocio	Seville	Andalucia
Switzerland	University Hospital Basel	Basel
Switzerland	University Hospital Bern	Bern
Switzerland	Cantonal Hospital Chur	Chur	Graubunden
Switzerland	Hopitaux Universitaires de Genève	Genève
Switzerland	CHUV	Lausanne
Switzerland	Epatocentro Ticino	Lugano
Switzerland	Canton Hospital St-Gallen	Saint Gallen
Switzerland	UniversitätsSpital Zürich	Zürich

Sponsors (9)

Lead Sponsor	Collaborator
Oriol Manuel	Cantonal Hospital Chur, Cantonal Hospital of St. Gallen, Fondazione Epatocentro Ticino, Hospitales Universitarios Virgen del Rocío, University Hospital, Basel, Switzerland, University Hospital, Geneva, University of Bern, University of Zurich

Countries where clinical trial is conducted

Spain,  Switzerland, 

References & Publications (5)

Koller MT, van Delden C, Müller NJ, Baumann P, Lovis C, Marti HP, Fehr T, Binet I, De Geest S, Bucher HC, Meylan P, Pascual M, Steiger J. Design and methodology of the Swiss Transplant Cohort Study (STCS): a comprehensive prospective nationwide long-term — View Citation

Kumar D, Campbell P, Hoschler K, Hidalgo L, Al-Dabbagh M, Wilson L, Humar A. Randomized Controlled Trial of Adjuvanted Versus Nonadjuvanted Influenza Vaccine in Kidney Transplant Recipients. Transplantation. 2016 Mar;100(3):662-9. doi: 10.1097/TP.00000000 — View Citation

Kumar D, Michaels MG, Morris MI, Green M, Avery RK, Liu C, Danziger-Isakov L, Stosor V, Estabrook M, Gantt S, Marr KA, Martin S, Silveira FP, Razonable RR, Allen UD, Levi ME, Lyon GM, Bell LE, Huprikar S, Patel G, Gregg KS, Pursell K, Helmersen D, Julian — View Citation

Manuel O, Estabrook M; AST Infectious Diseases Community of Practice. RNA respiratory viruses in solid organ transplantation. Am J Transplant. 2013 Mar;13 Suppl 4:212-9. doi: 10.1111/ajt.12113. — View Citation

Mombelli M, Rettby N, Perreau M, Pascual M, Pantaleo G, Manuel O. Immunogenicity and safety of double versus standard dose of the seasonal influenza vaccine in solid-organ transplant recipients: A randomized controlled trial. Vaccine. 2018 Oct 1;36(41):61 — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Vaccine response rate	Seroconversion rate for at least one viral antigen	day 28 after vaccination
Secondary	Influenza infection	PCR positive for influenza in a nasopharyngeal swab or other clinical specimen	Within 6 month after vaccination
Secondary	Seroprotection rates	Antibody levels >40 after vaccination	At day 28 and month 6 after vaccination
Secondary	Reactogenicity	Self-collected adverse events	within 28 days after vaccination
Secondary	Development of anti-HLA antibodies	De novo anti-HLA antibodies measured by Luminex	Within 6 months post vaccination